The population over 65 will increase to ~87 million by 2050. [Age alone is the greatest risk factor for developing Alzheimer's disease (AD) and other forms of neurodegeneration such as Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) or depression.] With no prevention or treatment, aged-related neurodegeneration could reach 11-16 million by 2050. In 2035, today's Veterans will be middle-aged, with health issues like those seen in aging Vietnam Veterans, complicated by comorbidities of posttraumatic stress disorder, traumatic brain injury, and polytrauma. During neurodegeneration, the brain demonstrates region- specific alterations in neuronal morphology, reduced structural plasticity and dendritic branching, and a decreased capacity to regenerate. Brain function is underpinned by both electrical activity and chemical communication between neurons; this communication between cells is necessary for re-establishing normal brain function in the AD brain. In addition to genetic modulation that initiate neuronal growth, other interventions such as 1) selective serotonin and dopamine reuptake inhibition (SDRI) to promote cAMP, or 2) [neurotrophin receptor agonism] may promote structural and functional plasticity and improve behavior in individuals afflicted with AD. Proper neuronal growth and guidance is dependent upon communication from extracellular signals (i.e., spatial information) through the plasma membrane. A key plasmalemmal `hub' that transduces the extracellular cues to the underlying cytoskeletal machinery are membrane/lipid rafts (MLR), discrete microdomains enriched in sphingolipids, cholesterol, and scaffolding protein caveolin-1 (Cav-1). Neuronal polarization and motility is dependent upon MLR localized in its leading edge. We have previously demonstrated that neuron-targeted Cav-1 over-expression (achieved by linking it to a neuron-specific synapsin promoter [SynCav1]): 1) enhances membrane cholesterol, MLR formation, and synaptic receptor expression and signaling (TrkB); 2) increases serotonin receptor (5-HT6) and dopamine receptor-mediated (D1R) cAMP formation; 3) promotes dendritic sprouting and arborization even in the presence of growth inhibitors. A recent seminal publication from our group demonstrates that direct delivery of SynCav1 into the brain augments structural and functional hippocampal neuroplasticity in adult mice (6 mo) and aged mice (20 mo) and improves hippocampal-dependent contextual fear learning and memory in both adult and aged mice. These results provide proof-of-concept evidence that by increasing expression of Cav-1 specifically in neurons, one can improve structural and functional neuroplasticity with positive behavioral outcome. This application seeks to determine whether SynCav1 can induce similar neuroplastic changes in differentiated human neuronal stem cells (NSCs) derived from induced pluripotent stem cells (iPSCs) and then to use SynCav1 in combination with SSRIs, SDRIs, or TrkB agonism to significantly augment the rate of behavioral improvement in AD mice. Our study will utilize a novel in vitro model of adult human differentiated neuronal stem cells (NSCs) derived form induced pluripotent stem cells (iPSCs) combined with quantum dot axonal transport time- lapse imaging to assess neuronal function, and in vivo genetic interventions, pharmacological, and exercise therapeutic techniques, electrophysiology, confocal and scanning electron microscopy, and motor and cognitive batteries. Completion of the proposed experiments could lead to the justification of using novel therapeutic interventions (small molecules, peptides, gene manipulation) that target Cav-1 and MLR for the purpose of combating AD-associated neurodegeneration or nerve trauma in the Veteran population.